3,5,6-trihydroxy androstane and pregnane compounds



Patented Feb. 27, 1940 PBEGNANE COMPOUNDS Karl Miescher, Riehen, and Werner Fischer,

Basel, Switzerland, assignors to the Society 1 of Chemical Industry in Basle, Basel, Switzerno Drawing. Application November 93 88. rial No.'174,906. lnswitzerland November .21, H

This invention is based on theiobservation that compounds of the androstane' and pregnane' series, having at least four substituents containing oxygen of which at least three are hydroxylgroups, exhibit true solubility in water.

Such compounds may be produced in many ways. Thus, by meansof known methods, there may be attached at the'carbon double linking of suitable monoor poly-unsaturated compounds of the androstane and pregnane series, which if desired may also containfree orsubstituted, for instance esterified or etherified, hydroxyland/or keto-- groups, a pair of hydroxyl-groups and if desired any ester or ether groups which may be present may be saponified. The hydroxyl-groups may be attached for instance by the action of hydrogen peroxide if desired in the presence of a catalyst such as an acid, a salt or osmium tetroxide or of osmium oxide alone or in the presence of an oxidizing agent or even with the aid of permanganate. It s also possible to start from oxygen, halogen or halogen .hydrine addition products of the said unsaturated compounds and for the purpose of opening the oxygen bridgeor for exchanging the halogen for a hydroxyl-group to treat the product in known manner, for example with a saponifying agent. Thus the oxide obtained by the reaction of the unsaturated compoundwith a peroxide such as benzoyl peroxide may be split by water alone or in presence of an'acid.

Furthermore, the keto-groups in suitablepolyketones or hydroxy-ketones of the saturated or unsaturated androstane or pregnane series, having at least four substituents containing oxygen in which hydroxyl-groups present may be free ormay contain substituents, may be converted into hydroxyl-groups wholly or in part with the aid of reducing agents, for instance. of hydrogen in the presence of a catalyst in an acid, neutral or alkaline medium. Suitable poly-ketones or hydroxy-kctones may be produced by the action of selenium dioxide or chromic acid on corresponding compounds having double carbon linkages and/or keto-grcups whereby the newly acquired oxygen enters in a-position to the existing double linkage or keto-groups.

The said methods of preparation may obviously be used in' conjunction with each other.

Suitable parent materials are, for instance, the dehydro-androsterones, androstene diols, 'testosterones, androstene'diones, pregnenolones, pregnene diols, progesterone, 1'7-vinyl-androstene- 3,17-diol or 17-vinyl-androstane-3,l7 -diol' (produced for example, from the corresponding hydroxyketones with the aid of vinyl bromide in i 3 Claims. (01.260-397) the presence of magnesium) ,jbis-dehydro compounds of the androstane'and pregnane series, '7- hydroxy or '7 keto-dehydroandrosterone, also oxygen, .halogen 'or halogen hydrine addition a products of correspondingly unsaturated compounds or the like as well as esters andif desired eno'lesters o'r eth'ers of these compounds.

Instead or compounds of the" androstane and pregnane seriesthere may also be used stereo-isomeridesjas parent materials.

The new compounds are as such physiologically active or may be converted into therapeutically active compounds.

The following examples illustrate the invention: r

a Example 1 2 grams of A5-trans-dehydroandrosterone acetate are dissolved in 10 cc. of glacial acetic'acid; there are added 2 cc. of hydrogen peroxide of 30 a per cent. strength'and the whole is heated on the Water bath for'2 hours. After this'treatment' the solution no longer gives a coloration with tetranitro'methane. The glacial acetic acid is distilled completely in. a vacuum and the oily residue is saponified in the course of 10 hours by means of cc. of a methyl alcoholic solution of 5 per cent. strength of caustic potash. The saponifying mass is diluted with water and extracted a few times by means .of boiling chloroform. After the chloroform solution has been dried over sodium sulfate and somewhat evaporated there crystallizes from it the 3,5,6-trihydroxy-androstanone-17 which is soluble in water but sparingly soluble in most organicsolvents. It melts at 300 C. while decomposing strongly. From acetone it crystallizes in slender needles.

Insteadof fione can start from M-trans-dehydroa'ndrosterone or an ester thereof or from the corresponding cis-compounds.

the mixture is allowed to stand for 40 hours at +5 C. The solution is now shaken with dilute cc. of chloroform are mixed at -l0 C. with a sodium carbonate solution to remove any acid constituents which may be present and after washing it with water is dried oversodium sulfate and evaporated. There are obtained 5.4 grams of a crude product which melts at 201-205 C. and gives no coloration with tetranitromethane. From this product one can obtain by means of acetone an oxide which melts at 229-230" C.

and crystallizes in thick columns. The mother a solves and the rest may be filtered, being in the form of beautiful crystals. Like the product ob -.1 tained by extracting the water withboiling chloroform these crystals can be "recrystallized-from acetone. The 3,5,6-trihydroxy-androstanonev(17) has the same properties as those of the compound obtained as described in Example 1.

Example '3 2 grams of A -androstene -3J7-dio1 diacetate are dissolved in 10 cc. of glacial acetic amen H the solution is mixed with 1.8 cc. of hydrogen peroxide of per cent. strength and the whole is heated for 2 hours on the water-bath; After 5 distilling-the glacial acetic acid in a vacuum the product is saponified by means of cc. of a methyl alcohol solution of 5 per cent strength of caustic potash. After the solution has been evaporated to a small bulk a little water is added and the 3,5,6,17-tetroxy-androstane which has been formed is extracted bymeans of chloroform. I

It may be recrystallized from acetone or ethyl acetate.

The same compound is obtained by starting from androstene diol and its mono-esters.

In similar manner there is obtained for example 3,5,6-trihydroxy-pregnane-ole- (20), 3,5,6-trihyroxy-pregnane-one- (20), 3,5,6,7-tetrahydroxyandrostane-l'l-ole. as well as-lZ-one and the like.

What we claim is:

:1,- l. The water-soluble 3,5,6-trihydroxy-andro- Co and \CHOH 2. The water-soluble 3,5,6-trihydroxy-andro-' member of the, group comprising oo and \CHOH v y 3 The. water-solublev 3,5,6-trihydro yfDregn'ane compounds having in the 20-position a. member of the group comprising oo and \CHOH KARL MIESCHER. WERNER FISCHER.

.15 stane compounds having in the 17-po'sition a 

